Substituted imidazoles as dual histamine H1 and H3 agonists or antagonists

Abstract

The present invention discloses novel substituted imidazole compounds which have either or dual histamine-H 1 and H 3 receptor antagonist activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such imidazoles as well as methods of using them to treat allergy, inflammatory and CNS-related diseases and others.

What is claimed is:  
     
       1. A compound, or an enantiomer, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt or solvate of said compound, with said compound having the general structure shown in Formula I:                    
       wherein 
       G is selected from the group consisting of C 1 -C 6  alkyl or a bond;  
       M is a moiety selected from the group consisting of —C═C—, —C≡C—, —C(═NR 7 )—NR 6 —, —NR 6 —C(═NR 7 )—, —NR 6 —C(O)—NR 6 —, —NR 6 —C(O)—O—, —O—C(O)—NR 6 —, —NR 6 —C(O)—, —C(O)—NR 6 —, —O—, —NR 6 —, —C(O)—, —N + R 6 R 8 —, and                    
       p is 1-6  
       V is C 1 -C 6  alkyl;  
       X and Y may be the same or different and are independently selected from the group consisting of N, CH, or N-oxide, with the proviso that at least one of X and Y is N or N-oxide;  
       R 1  and R 2  may each number 1-4 and are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, polyhalolower alkyl, —OH, —N(R 6 ) 2 , —NO 2 , —CN, —COOR 6 , —CONR 6 R 8 , and —NR 6 —C(O)—R 7 (wherein R 7  is not —OH or —CN);  
       R 3  is selected from hydrogen, lower alkyl, lower alkoxy, hydroxyl, polyhalolower alkyl, and a bond forming a double bond towards the moiety G when G is C 1 -C 6  alkyl;  
       R 4  and R 5  are independently selected from the group consisting of hydrogen, lower alkyl, and polyhalolower alkyl;  
       R 6  and R 8  are independently selected from hydrogen, lower alkyl, aralkyl, alkylaryl, polyhalolower alkyl, substituted or unsubstituted phenyl; and substituted or unsubstituted benzyl; and  
       R 7  is selected from H, OH, alkoxy, cyano, phenyl, substituted phenyl, benzyl, and substituted benzyl;  
       with the proviso that when G is a bond, M is not —NR 6 C(O)O—, and with the proviso that when G is a bond and when M is either —O— or —O—C(O)—NR 6 —, then one of X and Y is N; and with the further proviso that when R 3  is —OH or alkoxyl, and G is a bond, then M≠O or NR 6 . 
     
     
       2. The compound of  claim 1 , wherein R 4 ═R 5 ═H. 
     
     
       3. The compound of  claim 2 , wherein R 6  and R 7  are H or lower alkyl. 
     
     
       4. The compound of  claim 2 , wherein R 1  and R 2  are independently selected from H, halogen, hydroxy or lower alkoxy. 
     
     
       5. The compound of  claim 2 , wherein M is selected from the group consisting of —C(═NH)—NH—; —NH—C(═NH)—; —C(O)—NH—; —C(O)—N(CH 3 )—; —NH—; —N(CH 3 )—; —NHCO—; —N(CH 3 )—CO—; —NHC(═O)—NH—; —NHC(═O)—O—; —NH—C(═N—CN)—NH—; and —O—C(═O)—NH—. 
     
     
       6. The compound of  claim 5 , wherein R 1  and R 2  are H, halogen, hydroxy or alkoxy; and R 3  is H, lower alkyl or a bond forming a double bond towards moiety G. 
     
     
       7. The compound of  claim 6  wherein R 3 ═H, M is —NH—, —N(alkyl)—, —C(O)NH—, —C(═NH)NH—, —C(O)N(alkyl)—. 
     
     
       8. A composition comprising a compound of  claim 1 . 
     
     
       9. A pharmaceutical composition for use in treating inflammation, allergy, allergic rhinitis, congestion, or allergy-induced airway responses, said composition comprising as an active ingredient a compound of  claim 1 . 
     
     
       10. The composition of  claim 8  additionally comprising a pharmaceutically acceptable carrier. 
     
     
       11. A method of treating inflammation, allergy, nasal congestion, or allergy-induced airway responses, said method comprising administering to a mammalian patient in need of such treatment a pharmaceutical composition which comprises therapeutically effective amounts of a compound of  claim 1 . 
     
     
       12. A method of preparing a pharmaceutical composition for treating inflammation, allergy, nasal congestion, or allergy-induced airway responses, said method comprising bringing into intimate contact a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       13. A compound exhibiting H 3  antagonist activity, or an enantiomer, a stereoisomer or tautomer of said compound, or a pharmaceutically acceptable salt or solvate of said compound, said compound being selected from the compounds of structures listed below:                    
     
     
       14. A compound exhibiting both H 1  and H 3  antagonist activity, or an enantiomer, a stereoisomer or a tautomer of said compound, or pharmaceutically acceptable salt or a solvate of said compound, said compound being selected from the compounds of structures listed below:                  
                   
     
     
       15. A pharmaceutical composition for treating inflammation, allergy, nasal congestion, or allergy-induced airway responses, said composition comprising therapeutically effective amount of a compound of  claim 14  and a pharmaceutically acceptable carrier.